Scientists uncover molecular link between high salt and cognitive decline

A new study has identified a specific chain of molecular events that explains how a high-salt diet can contribute to cognitive decline. The research, published in the journal Advanced Science, reveals that consuming excess salt can disrupt a key signaling pathway in the brain, leading to the reduction of a protein essential for maintaining healthy connections between neurons and causing memory deficits in animal models.

Scientists have long recognized that high salt intake is a risk factor for cognitive problems, but the precise biological mechanisms have remained largely unclear. While some research has pointed to issues like reduced blood flow in the brain or inflammation, a team of researchers led by Cuiping Guo sought to investigate a more direct effect on the brain’s communication network.

They focused on synapses, the specialized junctions where neurons transmit signals to one another. The integrity of these connections is fundamental to learning and memory, and their dysfunction is a hallmark of many neurodegenerative diseases. The researchers hypothesized that a high-salt diet might directly damage these synaptic structures.

To test this idea, the scientific team conducted a series of experiments using rats. They divided the animals into two groups: one received a normal diet, while the other was fed a diet with a very high concentration of salt for nine weeks. Following this period, the rats underwent several behavioral tests designed to assess their learning and memory abilities. In one test, which evaluates spatial memory, rats had to learn the location of a hidden platform in a small pool of water. In another, their ability to recognize a new object was measured. The results from these tests showed a clear impairment in the rats that consumed the high-salt diet, as they struggled with memory-related tasks compared to the control group.

With the behavioral effects established, the investigators next examined the brains of the rats to identify the physical changes behind the memory loss. They focused on the hippocampus, a brain region known to be central to memory formation. By measuring the electrical activity between neurons in hippocampal tissue, they found that synaptic communication was significantly weaker in the high-salt group.

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Using powerful electron microscopes to visualize the synapses, they observed physical evidence of decay. The rats on the high-salt diet had fewer synapses overall, and the existing ones had smaller and less developed postsynaptic densities, which are complex protein structures on the receiving end of a synapse that are essential for processing signals.

To pinpoint the molecular cause of this synaptic damage, the researchers used a technique called RNA sequencing to analyze gene activity in the hippocampus. This method allowed them to see which genes were being turned up or down in response to the high-salt diet. The analysis revealed significant changes in genes related to synaptic function.

One protein, named SHANK1, stood out because its expression was substantially decreased in the rats fed excess salt. SHANK1 is a scaffolding protein, meaning it acts as an organizational hub at the synapse, holding other important proteins in place and ensuring the structure is stable and functional. Subsequent tests confirmed that the levels of SHANK1 protein were indeed much lower in the high-salt rats.

To determine if the loss of SHANK1 was a direct cause of the cognitive problems and not just a side effect, the researchers performed a follow-up experiment. They used a specially engineered virus to selectively reduce the amount of SHANK1 in the hippocampus of healthy rats that were on a normal diet. This intervention produced the same effects seen in the high-salt group. The rats with reduced SHANK1 developed synaptic dysfunction and performed poorly on memory tests. This result provided strong evidence that the decline in SHANK1 protein is a key contributor to the cognitive impairments induced by high salt consumption.

The team then worked to understand what was causing the reduction in SHANK1. They investigated a known cellular communication route called the PKA/CREB pathway. This pathway begins with a signaling molecule that activates an enzyme known as protein kinase A. This enzyme, in turn, activates a gene-regulating protein called cAMP-response element-binding protein, or CREB. The CREB protein functions like a switch that turns on the production of other proteins necessary for memory and synaptic health.

The investigation revealed that in the rats on the high-salt diet, the activity of protein kinase A was suppressed. This led to less activation of the CREB protein, which in turn meant that the gene for SHANK1 was not being turned on as it should be, resulting in lower protein levels.

Having identified this complete molecular pathway, the researchers tested whether they could reverse the damage. In a new experiment, they took rats that had been on a high-salt diet and injected a chemical that directly activates protein kinase A into their hippocampi. The treatment successfully restored the activity of the CREB protein and brought SHANK1 production back to normal levels. Remarkably, this molecular repair translated into functional recovery. The rats showed improved synaptic function and performed significantly better on memory tests, demonstrating that the damage caused by the high-salt diet could be reversed by targeting this specific pathway.

To further solidify the central role of the CREB protein in this process, the team conducted experiments in cultured neurons. They used genetically modified versions of the CREB protein, one that was permanently active and one that was permanently inactive. When the permanently active version was introduced into neurons, it prevented SHANK1 levels from dropping even when protein kinase A was blocked. Conversely, activating protein kinase A failed to increase SHANK1 when the permanently inactive version of CREB was present. This confirmed that the CREB protein is the essential link connecting protein kinase A signaling to the production of SHANK1.

While the study provides a detailed mechanism linking high salt intake to cognitive problems, the researchers note some limitations. The precise way in which high salt levels in the body lead to the initial suppression of protein kinase A activity in the brain is not yet fully understood and requires more investigation. The study also used a very high concentration of salt to induce effects within an experimental timeframe.

Future work could explore the impact of more moderate salt consumption over longer periods, which would more closely resemble typical human dietary patterns. As the experiments were conducted in rats, additional research will be needed to confirm that this same pathway is at play in humans. The findings suggest that this molecular pathway could be a promising target for developing therapies to protect against or treat cognitive dysfunction associated with diet.

The study, “Long Term High-Salt Diet Induces Cognitive Impairments via Down-Regulating SHANK1,” was authored by Cuiping Guo, Yuanyuan Li, Wensheng Li, Tongrui Wu, Yi Liu, Yacoubou Abdoul Razak Mahaman, Jianzhi Wang, Rong Liu, Wei Liu, Hui Shen, and Xiaochuan Wang.